Benzimidazolone compounds

ABSTRACT

Disclosed are compounds of the formula (I):  
                 
 
wherein A, B, C, M 1 -M 4 , R, R 1 , R 2  and n are as described herein.

This application claims priority from U.S. Provisional Application Ser.No. 60/284,665, filed Apr. 18, 2001, the disclosure of which is herebyincorporated by reference.

BACKGROUND OF THE INVENTION

Chronic pain is a major contributor to disability and is the cause of anuntold amount of suffering. The successful treatment of severe andchronic pain is a primary goal of the physician with opioid analgesicsbeing preferred drugs.

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes were designated as μ, δ and κ.As opiates had a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

Recent experimentation has led to the identification of a cDNA encodingan opioid receptor-like (ORL1) receptor with a high degree of homologyto the known receptor classes. This newly discovered receptor wasclassified as an opioid receptor based only on structural grounds, asthe receptor did not exhibit pharmacological homology. It was initiallydemonstrated that non-selective ligands having a high affinity for μ, δand κ receptors had low affinity for the ORL1. This characteristic,along with the fact that an endogenous ligand had not yet beendiscovered, led to the term “orphan receptor”.

Subsequent research led to the isolation and structure of the endogenousligand of the ORL1 receptor. This ligand is a seventeen amino acidpeptide structurally similar to members of the opioid peptide family.

The discovery of the ORL1 receptor presents an opportunity in drugdiscovery for novel compounds which can be administered for painmanagement or other syndromes modulated by this receptor.

All documents cited herein, including the foregoing, are incorporated byreference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly an object of certain embodiments of the presentinvention to provide new compounds which exhibit affinity for the ORL1receptor.

It is an object of certain embodiments of the present invention toprovide new compounds which exhibit affinity for the ORL1 receptor andone or more of the μ, δ or κ receptors.

It is an object of certain embodiments of the present invention toprovide new compounds for treating a patient suffering from chronic oracute pain by administering a compound having affinity for the ORL1receptor.

It is an object of certain embodiments of the present invention toprovide new compounds which have agonist activity at the μ, δ and κreceptors which is greater than compounds currently available e.g.morphine.

It is an object of certain embodiments of the present invention toprovide methods of treating chronic and acute pain by administeringcompounds which have agonist activity at the μ, d and k receptors whichis greater than compounds currently available.

It is an object of certain embodiments of the present invention toprovide methods of treating chronic and acute pain by administeringnon-opioid compounds which have agonist activity at the μ, δ and κreceptors and which produce less side effects than compounds currentlyavailable.

It is an object of certain embodiments of the present invention toprovide compounds useful as analgesics, anti-inflammatories, diuretics,anesthetics, neuroprotective agents, anti-hypertensives,anti-anxioltics; agents for appetite control; hearing regulators;anti-tussives, anti-asthmatics, modulators of locomotor activity,modulators of learning and memory, regulators of neurotransmitter andhormone release, kidney function modulators, anti-depressants, agents totreat memory loss due to Alzheimer's disease or other dementias,anti-epileptics, anti-convulsants, agents to treat withdrawal fromalcohol and drugs of addiction, agents to control water balance, agentsto control sodium excretion and agents to control arterial bloodpressure disorders and methods for administering said compounds.

The compounds of the present invention are useful for modulating apharmacodynamic response from one or more opioid receptors (ORL-1, μ, δand κ) centrally and/or peripherally. The response can be attributed tothe compound stimulating (agonist) or inhibiting (antagonist) the one ormore receptors. Certain compounds can stimulate one receptor (e.g., a μagonist) and inhibit a different receptor (e.g., an ORL-1 antagonist).

Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof. The presentinvention in certain embodiments comprises compounds having the generalformula (I):

wherein

A is a saturated or partially saturated ring;

R is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkylC₁₋₄alkyl-, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy-, C₁₋₁₀ alkylsubstituted with 1-3 halogen, C₃₋₁₂ cycloalkyl substituted with 1-3halogen, C₃₋₁₂ cycloalkylC₁₋₄alkyl- substituted with 1-3 halogen, C₁₋₁₀alkoxy substituted with 1-3 halogen, C₃₋₁₂ cycloalkoxy- substituted with1-3 halogen, —COOV₁, —C₁₋₄COOV₁, —CH₂OH, —SO₂N(V₁)₂, hydroxyC₁₋₁₀alkyl-,hydroxyC₃₋₁₀cycloalkyl-, cyanoC₁₋₁₀ alkyl-, cyanoC₃₋₁₀cycloalkyl-,—CON(V₁)₂, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, sulfonylaminoC₁₋₁₀alkyl-,diaminoalkyl-, -sulfonylC₁₋₄alkyl, a 6-membered heterocyclic ring, a6-membered heteroaromatic ring, a 6-membered heterocyclicC₁₋₄alkyl-, a6-membered heteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a6-membered aromaticC₁₋₄alkyl-, a 5-membered heterocyclic ring optionallysubstituted with an oxo or thio, a 5-membered heteroaromatic ring, a5-membered heterocyclicC₁₋₄alkyl- optionally substituted with an oxo orthio, a 5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₅(═O)W₁, —C₁₋₅(═NH)W₁,—C₁₋₅NHC(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, wherein W₁ is hydrogen,C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH,amino, C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a 5-memberedheteroaromatic ring optionally substituted with 1-3 lower alkyl;

wherein each V₁ is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, benzyl and phenyl;

n is an integer from 0 to 3;

M₁, M₂, M₃ and M₄ are each independently N, NH, CH or CH₂, up to amaximum of 3 N or NH;

D, B and C are independently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH, —NHSO₂, hydroxyC₁₋₁₀alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,acylamino-, acylaminoalkyl-, amide, sulfonylaminoC₁₋₁₀alkyl-, or D-B cantogether form a C₂₋₆bridge, or B-C can together form a C₃₋₇, bridge, orD-C can together form a C₁₋₅ bridge;

Z is selected from the group consisting of a bond, straight or branchedC₁₋₆ alkylene, —NH—, —CH₂O—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—,—NHCH₂CO—, —CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, —O— and—HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted orsubstituted with one or more lower alkyl, hydroxy, halo or alkoxy group;

R₁ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino-,C₃₋₁₀cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁, cyano, cyanoC₁₋₁₀alkyl-,cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,benzyl, C₃₋₁₂ cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl orheteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ringsystem, and a spiro ring system of the formula (II):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; and wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, or benzyl of R₁ is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl-,cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-membered heteroaromaticC₁₋₄alkyl-,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl-, C₁₋₁₀ alkoxy-, and cyano; andwherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, or spiro ring system of the formula (II) isoptionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano;

R₂ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl C₃₋₁₂cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substitutedwith an oxo, amino, alkylamino or dialkylamino group;

and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds havingthe formula (IA):

wherein

A is a saturated or partially saturated ring;

n is an integer from 0 to 3;

Z is selected from the group consisting of a bond, —CH₂—, —NH—, —CH₂O—,—CH₂CH₂—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, —CH₂CO—,—COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, and —HC═CH—, wherein the carbonand/or nitrogen atoms are unsubstituted or substituted with a loweralkyl, halogen, hydroxy or alkoxy group;

R is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, and C₃₋₁₂cycloalkyl;

R₁ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, benzyl, C₃₋₁₂ cycloalkenyl, a monocyclic, bicyclicor tricyclic aryl or heteroaryl ring, a hetero-moncyclic ring, aheterobicyclic ring system, and a spiro ring system of the formula (II):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, or benzyl is optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy,said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, and cyano;

wherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,heterobicyclic ring system, and spiro ring system of the formula (II)are optionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano;

R₂ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl and halogen, said alkyl optionally substituted with an oxogroup;

and pharmaceutically acceptable salts thereof.

In certain preferred embodiments of formula (I) or (IA), the R₁ alkyl ismethyl, ethyl, propyl, butyl, pentyl, or hexyl.

In certain preferred embodiments of formula (I) or (IA), the R₁cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, or norbornyl.

In other preferred embodiments of formula (I) or (IA), the R₁ bicyclicring system is naphthyl. In other preferred embodiments of formula (I)or (IA), the R₁ bicyclic ring system is tetrahydronaphthyl, ordecahydronaphthyl and the R₁ tricyclic ring system isdibenzocycloheptyl. In other preferred embodiments R₁ is phenyl orbenzyl.

In other preferred embodiments of formula (I) or (IA), the R₁ bicyclicaromatic ring is a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of formula (I) or (IA), the R₁ bicyclicaromatic ring is a 9-membered ring, preferably indenyl.

In certain embodiments of formula (I) or (IA), Z is a bond, methyl, orethyl.

In certain embodiments of formula (I) or (IA), the Z group is maximallysubstituted as not to have any hydrogen substitution on the base Zgroup. For example, if the base Z group is —CH₂—, substitution with twomethyl groups would remove hydrogens from the —CH₂— base Z group.

In other preferred embodiments of formula (I) or (IA), n is 0.

In certain embodiments, A is a saturated ring.

In certain embodiments of formula (I) or (IA), X₁ and X₂ are both O.

In certain embodiments of formula (I), R is —CH₂C═ONH₂, —C(NH)NH₂,pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C(═O)CH₃,—CH₂CH₂NHC(═O)CH₃, —SO₂CH₃, CH₂CH₂NHSO₂CH₃, furanylcarbonyl-,methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-,trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, ordiazolemethyl-.

In certain embodiments of formula (I), ZR₁ is cyclohexylethyl-,cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-,phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-,pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-,tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-,thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-,isopropoxybutyl-, hexyl-, or oxocanylpropyl-.

In certain embodiments of formula (I), at least one of ZR₁ or R is—CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-, NH₂SOmethyl-,aminocarbonylmethyl-, C₁₋₄alkylaminocarbonylmethyl-, ordiC₁₋₄alkylaminocarbonylmethyl-.

In certain embodiments of formula (I), ZR₁ is 3,3 diphenylpropyloptionally substituted at the 3 carbon of the propyl with —COOV₁,tetrazolylC₀₋₄alkyl-, cyano-, aminocarbonyl-, C₁₋₄alkylaminocarbonyl-,or diC₁₋₄alkylaminocarbonyl-.

In alternate embodiments in formula (I) or (IA), ZR₁ can be thefollowing

wherein

Y₁ is R₃—(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl, R₆—(C₃-C₁₂)cyclo-alkyl,R₇—(C₃-C₇)heterocycloalkyl, —CO₂(C₁-C₆)alkyl, CN or —C(O)NR₈R₉; Y₂ ishydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; or Y₁, Y₂ and Y₃,together with the carbon to which they are attached, form one of thefollowing structures:

wherein r is 0 to 3; w and u are each 0-3, provided that the sum of wand u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring Eis a fused R₄-phenyl or R₅-heteroaryl ring;

R₁₀ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ and—(C₁-C₆)alkyl-NR₈R₉;

R₁₁ is 1 to 3 substituents independently selected from the groupconsisting of R₁₀, —CF₃, —OCF₃, NO₂ and halo, or R₁₁ substituents onadjacent ring carbon atoms may together form a methylenedioxy orethylenedioxy ring;

R₈ and R₉ are independently selected from the group consisting ofhydrogen, (C₁-C₆) alkyl, (C₃-C₁₂)cycloalkyl, aryl and aryl(C₁-C₆)alkyl;

R₃ is 1 to 3 substituents independently selected from the groupconsisting of H, R₄-aryl, R₆—(C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈R₉, —OR₁₂ and —S(O)₀₋₂R₁₂;

R₆ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, R₄-aryl, —NR₈R₉, —OR₁₂ and —SR₁₂;

R₄ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl,(C₃-C₁₂)cycloalkyl, —CN, —CF₃, —OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₁,—(C₁-C₆)alkyl —NR₈R₉, —NHSO₂R₈, —SO₂N(R₁₄)₂, —SO₂R₈, —SOR₈, —SR₈, —NO₂,—CONR₈R₉, —NR₉COR₈, —COR₈, —COCF₃, —OCOR₈, —OCO₂R₈, —COOR₈,—(C₁-C₆)alkyl-NHCOOC(CH₃)₃, —(C₁-C₆)alkyl-NHCOCF₃,—(C₁-C₆)alkyl-NHSO₂—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-NHCONH-(C₁-C₆)-alkyl and

wherein f is 0 to 6; or R₄ substituents on adjacent ring carbon atomsmay together form a methylenedioxy or ethylenedioxy ring;

R₅ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl,(C₃-C₁₂)cycloalkyl, —CN, —CF₃, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉,—(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈, —SO₂N(R₁₄)₂, —NO₂, —CONR₈R₉, —NR₉COR₈,—COR₈, —OCOR₈, —OCO₂R₈ and —COOR₈;

R₇ is H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ or—(C₁-C₆)alkyl-NR₈R₉;

R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, —(C₁-C₆)alkyl-OR₈, —(C₁-C₆)alkyl-NR₈R₉,—(C₁-C₆)alkyl-SR₈, or aryl (C₁-C₆)alkyl;

R₁₃ is 1-3 substituents independently selected from the group consistingof H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo;

R₁₄ is independently selected from the group consisting of H,(C₁-C6)alkyl and R₁₃—C₆H₄—CH₂—.

As used herein, the term “alkyl” means a linear or branched saturatedaliphatic hydrocarbon group having a single radical and 1-10 carbonatoms. Examples of alkyl groups include methyl, propyl, isopropyl,butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branchedalkyl means that one or more alkyl groups such as methyl, ethyl orpropyl, replace one or both hydrogens in a —CH₂— group of a linear alkylchain. The term “lower alkyl” means an alkyl of 1-3 carbon atoms.

The term “alkoxy” means an “alkyl” as defined above connected to anoxygen radical.

The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3-12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyland norbornyl.

The term “alkenyl” means a linear or branched aliphatic hydrocarbongroup containing a carbon-carbon double bond having a single radical and2-10 carbon atoms. A “branched” alkenyl means that one or more alkylgroups such as methyl, ethyl or propyl replace one or both hydrogens ina —CH₂— or —CH═ linear alkenyl chain. Exemplary alkenyl groups includeethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl,2-propenyl, heptenyl, octenyl and decenyl.

The term “cycloalkenyl” means a non-aromatic monocyclic or multicyclichydrocarbon ring system containing a carbon-carbon double bond having asingle radical and 3 to 12 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl orcycloheptenyl. An exemplary multicyclic cycloalkenyl ring isnorbornenyl.

The term “aryl” means a carbocyclic aromatic ring system containing one,two or three rings which may be attached together in a pendent manner orfused, and containing a single radical. Exemplary aryl groups includephenyl, naphthyl and acenaphthyl.

The term “heterocyclic” means cyclic compounds having one or moreheteroatoms (atoms other than carbon) in the ring, and having a singleradical. The ring may be saturated, partially saturated or unsaturated,and the heteroatoms may be selected from the group consisting ofnitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered hetero-monocyclic groups containing 1to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl; saturated 3- to 6-membered hetero-monocyclic groupscontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asmorpholinyl; saturated 3- to 6-membered hetero-monocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolidinyl. Examples of partially saturated heterocyclic radicalsinclude dihydrothiophene, dihydropyran, and dihydrofuran. Otherheterocyclic groups can be 7 to 10 carbon rings substituted withheteroatoms such as oxocanyl and thiocanyl. When the heteroatom issulfur, the sulfur can be a sulfur dioxide such as thiocanyldioxide.

The term “heteroaryl” means unsaturated heterocyclic radicals, wherein“heterocyclic” is as previously described. Exemplary heteroaryl groupsinclude unsaturated 3 to 6 membered hetero-monocyclic groups containing1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, andpyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated 3to 6-membered hetero-monocyclic groups containing an oxygen atom, suchas furyl; unsaturated 3 to 6 membered hetero-monocyclic groupscontaining a sulfur atom, such as thienyl; unsaturated 3 to 6 memberedhetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; and unsaturated condensed heterocyclic group containing 1 to2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. Theterm “heteroaryl” also includes unsaturated heterocyclic radicals,wherein “heterocyclic” is as previously described, in which theheterocyclic group is fused with an aryl group, in which aryl is aspreviously described. Exemplary fused radicals include benzofuran,benzdioxole and benzothiophene.

As used herein, the term “heterocyclicC₁₋₄alkyl”,“heteroaromaticC₁₋₄alkyl” and the like refer to the ring structurebonded to a C₁₋₄ alkyl radical.

All of the cyclic ring structures disclosed herein can be attached atany point where such connection is possible, as recognized by oneskilled in the art.

As used herein, the term “patient” includes a human or an animal such asa companion animal or livestock.

As used herein, the term “halogen” includes fluoride, bromide, chloride,iodide or alabamide.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonatessuch as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts such as arginate, asparginate, glutamate and thelike.

The invention disclosed herein is also meant to encompass all prodrugsof the disclosed compounds. Prodrugs are considered to be any covalentlybonded carriers which release the active parent drug in vivo.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also meant to encompass the disclosedcompounds being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The term “modulate” as used herein with respect to the ORL-1 receptormeans the mediation of a pharmacodynamic response (e.g., analgesia) in asubject from (i) inhibiting or activating the receptor, or (ii) directlyor indirectly affecting the normal regulation of the receptor activity.Compounds which modulate the receptor activity include agonists,antagonists, mixed agonists/antagonists and compounds which directly orindirectly affect regulation of the receptor activity.

Certain preferred compounds of the invention include:

1-[1-benzyl-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(benzyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-benzyl-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(4-propylcyclohexyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(5-methylhex-2-yl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(cyclooctyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

1-[1-(cyclooctylmethyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(benzyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;

3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;and

pharmaceutically acceptable salts thereof and solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention can be administered to anyonerequiring modulation of the opioid and ORL1 receptors. Administrationmay be orally, topically, by suppository, inhalation, or parenterally.

The present invention also encompasses all pharmaceutically acceptablesalts of the foregoing compounds. One skilled in the art will recognizethat acid addition salts of the presently claimed compounds may beprepared by reaction of the compounds with the appropriate acid via avariety of known methods.

Various oral dosage forms can be used, including such solid forms astablets, gelcaps, capsules, caplets, granules, lozenges and bulk powdersand liquid forms such as emulsions, solution and suspensions. Thecompounds of the present invention can be administered alone or can becombined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

When the compounds of the present invention are incorporated into oraltablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions arid/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms, are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986). Techniques' and compositions for making solid oraldosage forms are described in Pharmaceutical Dosage Forms: Tablets(Lieberman, Lachman and Schwartz, editors) 2nd edition, published byMarcel Dekker, Inc. Techniques and compositions for making tablets(compressed and molded), capsules (hard and soft gelatin) and pills arealso described in Remington's Pharmaceutical Sciences (Arthur Osol,editor), 1553B1593 (1980). Techniques and composition for making liquidoral dosage forms are described in Pharmaceutical Dosage Forms: DisperseSystems, (Lieberman, Rieger and Banker, editors) published by MarcelDekker, Inc.

When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

In certain embodiments, the compounds of the present invention can beused in combination with at least one other therapeutic agent.Therapeutic agents include, but are not limited to, μ-opioid agonists;non-opioid analgesics; non-steroid antiinflammatory agents; Cox-IIinhibitors; antiemetics; β-adrenergic blockers; anticonvulsants;antidepressants; Ca2+-channel blockers; anticancer agent and mixturesthereof.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination with ap-opioid agonist. μ-opioid agonists, which may be included in theformulations of the present invention include but are not limited toinclude alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

In certain preferred embodiments, the μ-opioid agonist is selected fromcodeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,dihydromorphine, morphine, tramadol, oxymorphone, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

In another embodiment of the invention, the medicament comprises amixture of a Cox-II inhibitor and an inhibitor of 5-lipoxygenase for thetreatment of pain and/or inflammation. Suitable Cox-II inhibitors and5-lipoxygenase inhibitors, as well as combinations thereof are describedin U.S. Pat. No. 6,136,839, which is hereby incorporated by reference inits entirety. Cox-II inhibitors include, but are not limited torofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide, meloxicam,6-MNA, L-745337, nabumetone, nimesulide, NS-398, SC-5766, T-614,L-768277, GR-253035, JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387,NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib, valdecoxiband parecoxib or pharmaceutically acceptable salts, enantiomers ortautomers thereof.

The compounds of the present invention can also be combined in dosageforms with non-opioid analgesics, e.g., non-steroidal anti-inflammatoryagents, including aspirin, ibuprofen, diclofenac, naproxen,benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam,pharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics which may be included in the dosage formsof the present invention include the following, non-limiting, chemicalclasses of analgesic, antipyretic, nonsteroidal antiinflammatory drugs:salicylic acid derivatives, including aspirin, sodium salicylate,choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylicacid, sulfasalazine, and olsalazin; para-aminophennol derivativesincluding acetaminophen; indole and indene acetic acids, includingindomethacin, sulindac, and etodolac; heteroaryl acetic acids, includingtolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates),including mefenamic acid, and meclofenamic acid; enolic acids, includingoxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone,oxyphenthartazone); and alkanones, including nabumetone. For a moredetailed description of the NSAIDs that may be included within themedicaments employed in the present invention, see Paul A. InselAnalgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed inthe treatment of Gout in Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 617-57 (Perry B. Molinhoff and Raymond W. Ruddon, Eds.,Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic andAnti-Inflammatory Drugs in Remington: The Science and Practice ofPharmacy Vol II, 1196-1221 (A. R. Gennaro, Ed. 19th Ed. 1995) which arehereby incorporated by reference in their entireties.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withantimigraine agents. Antimigraine agents include, but are not limitedto, alpiropride, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate,fonazine, lisuride, lomerizine, methysergide oxetorone, pizotyline, andmixtures thereof.

The other therapeutic agent can also be an adjuvant to reduce anypotential side effects such as, for example, an antiemetic agent.Suitable antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine,sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine,tropisetron, and mixtures thereof.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withβ-adrenergic blockers. Suitable β-adrenergic blockers include, but arenot limited to, acebutolol, alprenolol, amosulabol, arotinolol,atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol,bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrinehydrochloride, butofilolol, carazolol, carteolol, carvedilol,celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol,indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol,moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol,oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol,sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol,toliprolol, and xibenolol.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withanticonvulsants. Suitable anticonvulsants include, but are not limitedto, acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withantidepressants. Suitable antidepressants include, but are not limitedto, binedaline, caroxazone, citalopram, dimethazan, fencamine,indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withCa2+-channel blockers. Suitable Ca2+-channel blockers include, but arenot limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil,mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine,aranidipine, barnidipine, benidipine, cilnidipine, efonidipine,elgodipine, felodipine, isradipine, lacidipine, lercanidipine,manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine,lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withanticancer agents. Suitable anticancer agents include, but are notlimited to, acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

The compounds of the present invention and the other therapeutic agentcan act additively or, more preferably, synergistically. In a preferredembodiment, a composition comprising a compounds of the presentinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition orin a different composition from that comprising the compounds of thepresent invention. In another embodiment, a composition comprising thecompounds of the present invention is administered prior to orsubsequent to administration of another therapeutic agent.

The compounds of the present invention when administered, e.g., via theoral, parenteral or topical routes to mammals, can be in a dosage in therange of about 0.01 mg/kg to about 3000 mg/kg body weight of the patientper day, preferably about 0.01 mg/kg to about 1000 mg/kg body weight perday administered singly or as a divided dose. However, variations willnecessarily occur depending upon the weight and physical condition(e.g., hepatic and renal function) of the subject being treated, theaffliction to be treated, the severity of the symptoms, the route ofadministration, the frequency of the dosage interval, the presence ofany deleterious side-effects, and the particular compound utilized,among other things.

The compounds of the present invention preferably have a bindingaffinity K_(i) for the human ORL-1 receptor of about 500 nM or less; 100nM or less; 50 nM or less; 20 nM or less or 5 nM or less. The bindingaffinity K_(i) can be measured by one skilled in the art by an assayutilizing membranes from recombinant HEK-293 cells expressing the humanopioid receptor-like receptor (ORL-1) as described below.

The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLE 1 Synthesis of “trans” Head Groups

Procedure:

A mixture of compound 1 (22.8 g, 200 mmol), compound 2 (19.9 g, 100mmol) and Na(OAc)₃BH (29.7 g, 140 mmol) in 300 mL 1,2-dichloroethane wasstirred overnight. The reaction was quenched with aqueous K₂CO₃. Themixture was extracted with Et₂O (3×), and the organic extracts weredried over K₂CO₃, filtered and the solvent was evaporated. The crudeproduct was purified by column chromatography (10% Et₃N, 40% EtOAc inhexane, then 10% Et₃N, 90% EtOAc, and then 10% MeOH, 90% EtOAc) to givepure 3 as a solid (18.80 g, 63.6%).

MS: m/z 298.3 (M+1)

¹H-NMR (CDCl₃): d 0.90 (m, 1H), 1.05-1.40 (m, 6H), 1.45 (s, 9H),1.68-1.80 (m, 5H), 1.88 (m, 2H), 2.05 (m, 1H), 2.15 (m, 1H), 2.30 (m,1H), 2.70-2.90 (m, 3H), 4.00 (b, 2H).

To a solution of compound 3 (18.8 g, 63 mmol) in 50 mL of CH₃CN wasadded 1,1′-carbonyldiimidazole (12.82 g, 79 mmol). Gas was evolved andthe mixture became a slurry in a few min and then a solid after 10 min.After 2 hr, the solid was dissolved in CH₂Cl₂ and washed with H₂O, driedover K₂CO₃ and filtered. The solvent was evaporated to give 4 as a whitesolid (18.0 g, 88.5%). This material was used directly in subsequentnext steps.

¹H-NMR (CDCl₃): d 1.30-1.50 (m, 13H), 1.55-1.75 (m, 8H), 1.80 (m, 2H),1.95 (m, 1H), 2.15 (m, 1H), 2.98 (m, 2H), 3.85 (m, 1H), 4.50 (bs, 1H).

To a solution of compound 4 (6.25 g, 19.3 mmol) in 70 mL of CH₂Cl₂ wasadded 20 mL of TFA. The mixture was stirred for 2 hr and then thesolvent and TFA were evaporated. The residue was dissolved in CH₂Cl₂,washed with saturated aqueous K₂CO₃ solution. The organic layer wasdried over K₂CO₃ and filtered. Evaporation of solvent gave 5 as a solid(3.50 g, 81.2%).

MS: m/z 224.2 (M+1)

¹H-NMR (CDCl₃): d 1.30-1.50 (m, 4H), 1.60-1.85 (m, 6H), 1.90 (b, 1H),1.25 (b, 1H) 1.65 (dq, 2H), 2.90-3.20 (m, 4H), 4.75 (m, 1H), 4.45 (b,1H).

To a suspension of NaH (60% oil dispersion, 1.0 g, 24 mmol) in 30 mL ofDMF was added compound 4 (6.46 g, 20 mmol) in 15 mL of DMF. After 5minutes, EtI (3.70 g, 24 mmol) was added to the reaction mixture. Themixture was stirred overnight, quenched with H₂O and extracted withCH₂Cl₂. The organic extracts were dried over K₂CO₃ and filtered.Evaporation of the solvent provided 6 (6.20 g, 88.2%). This material wasused directly in the next step.

LC: 94.6%

MS: m/z 352.2 (M+1)

¹H-NMR (CDCl₃): d 1.07 (t, 3H), 1.30-1.40 (m, 4H), 1.50 (s, 9H),1.60-1.77 (m, 6H), 1.80 (m, 2H), 2.05 (m, 1H), 2.15 (m, 1H), 2.70-2.90(m, 4H), 3.20 (m, 2H), 3.90 (m, 1H).

To a solution of compound 6 (6.10 g, 17.36 mmol) in 70 mL of CH₂Cl₂ wasadded 20 mL of TFA. The mixture was stirred for 2 hr and then thesolvent and TFA were evaporated. The residue was dissolved in CH₂Cl₂,washed with saturated aqueous K₂CO₃ solution. The organic layer wasdried over K₂CO₃ and filtered. Evaporation of solvent gave 7 as an oil(3.32 g, 76.1%).

¹H-NMR (CDCl₃): d 1.05 (t, 3H), 1.25-1.45 (m, 4H), 1.55-1.75 (m, 4H),1.80 (m, 2H), 2.00 (b, 1H), 2.25 (b, 1H), 2.60-2.75 (m, 3H), 2.80 (m,1H), 3.10 (t, 2H), 3.25 (m, 2H), 3.75 (m, 1H).

EXAMPLE 2 Synthesis of “cis” Head Groups

Procedure:

In a manner similar to the preparation of 7, compound 12 was prepared.

EXAMPLE 3 Attachment of Tail Groups

Tail groups were attached to the head groups according to the followingprocedures:

General Procedure for Alkylation:

To a solution of the amine (1 eq) and triethylamine (1 eq) indimethylformamide, was added 1 eq of alkyl bromide or chloride in oneportion. The mixture was stirred and heated at 80° C. over night. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography to give the pure product.

General Procedure for Reductive Amination:

To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid(1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in oneportion. The mixture was stirred over night at room temperature. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography to give the pure product.

The following compounds were prepared by attaching the tail groups usingthe general procedures described:

-   1-[1-benzyl-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

LC: 95%

MS: m/z

¹H NMR (CDCl₃): d 1.10-2.90 (m, 18H), 3.5 (s, 2H), 3.70 (m, 1H), 7.25(m, 5H).

-   1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 364.2 (M+1)

¹H-NMR (CDCl₃): d 1.35-2.00 (m, 11H), 2.10 (m, 2H), 2.35 (m, 1H),2.95-3.10 (m, 4H), 3.70 (s, 2H), 3.80 (m, 1H), 4.40 (s, 1H), 7.50 (m,3H), 7.70 (s, 1H), 7.80 (m, 3H).

-   1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 418.3 (M+1)

¹H-NMR (CDCl₃): d 1.30-2.00 (m, 15H), 2.28 (m, 4H), 2.80-3.05 (m, 3H),3.75 (m, 1H), 3.92 (t, 1H), 4.40 (b, 1H).

-   1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 348.3 (M+1)

¹H-NMR (CDCl₃): d 0.85 (m 3H), 1.10-1.70 (m, 20H), 1.78 (m, 5H), 1.92(m, 1H), 2.10-2.40 (m, 3H), 3.00 (m, 3H), 3.75 (m, 1H), 4.38 (b, 1H).

-   1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 322.3 (M+1)

¹H-NMR (CDCl₃): d 0.80-1.00 (m, 9H), 1.10-1.85 (m, 15H), 1.95 (m, 1H),2.20-2.45 (m, 3H), 2.52 (m, 1H), 2.78 (m, 2H), 3.00 (m, 2H), 3.75 (m,1H), 4.40 (b, 1H).

-   1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 360.3 (M+1)

¹H-NMR (CDCl₃): d 0.80-1.10 (m, 2H), 1.20-2.00 (m, 25H), 2.20-2.60 (m,4H), 2.85-3.15 (m, 4H), 3.75 (m, 1H), 4.40 (b, 1H).

-   1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 334.3 (M+1)

¹H-NMR (CDCl₃): d 1.20-1.90 (m, 24H), 1.95 (m, 1H), 2.35 (m, 3H), 2.55(m, 1H), 2.80 (m, 2H), 3.00 (m, 2H), 3.75 (m, 1H), 4.45 (s, 1H).

-   1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 348.3 (M+1)

¹H-NMR (CDCl₃): d 0.85 (m, 6H), 0.90-2.00 (m, 21H), 2.05-2.40 (m, 4H),3.00 (m, (m, 4H), 3.75 (m, 1H), 4.40 (b, 1H).

-   1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 348.3 (M+1)

¹H-NMR (CDCl₃): d 1.20 (m, 2H), 1.30-1.70 (m, 19H), 1.78 (m, 4H), 1.95(m, 3H), 2.05 (m, 2H), 2.3 (m, 1H), 2.90 (m, 2H), 3.00 (m, 2H), 3.75 (m,1H), 4.40 (b, 1H).

-   3-ethyl-1-[1-(benzyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 342.2 (M+1)

¹H-NMR (CDCl₃): d 1.02 (t, 3H), 1.40 (m, 4H), 1.60-1.72 (m, 2H), 1.80(m, 4H), 2.08 (m, 3H), 2.30 (m, 1H), 2.75 (m, 1H), 2.88 (m, 3H), 3.20(m, 2H), 3.50 (s, 2H), 3.80 (m, 1H), 7.25-7.35 (m, 5H).

-   3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 392.2

¹H-NMR (CDCl₃): d 1.05 (t, 3H), 1.30-1.90 (m, 8H), 2.00-2.15 (m, 3H),2.30 (m, 1H), 2.60 (m, 2H), 2.75 (m, 1H), 2.90 (m, 1H), 2.95 (m, 2H),3.20 (m, 2H), 3.65 (s, 2H), 3.80 (m, 1H), 7.48 (m, 3H), 7.70 (s, 1H),7.80 (m, 3H).

-   3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 446.3 (M+1)

¹H-NMR (CDCl₃): d 1.02 (t, 3H), 1.15 (m, 1H), 1.35 (m, 4H), 1.65-1.85(m, 5H), 1.90-2.05 (m, 3H), 2.25 (m, 4H), 2.6-2.78 (m, 2H), 2.80-2.95(m, 3H), 3.20 (m, 2H), 3.75 (m, 1H), 3.95 (m, 1H), 7.15-7.30 (m, 10H).

-   3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 376.3 (M+1)

¹H-NMR (CDCl₃): d 0.85 (m, 3H), 1.06 (t, 3H), 1.15-1.90 (m, 23H), 2.10(m, 1H), 2.10-2.35 (m, 4H), 2.74 (m, 1H), 2.85 (m, 1H), 2.99 (m, 2H),3.23 (m, 2H), 3.75 (m, 1H).

-   3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 350.3 (M+1)

¹H-NMR (CDCl₃): d 0.85 (d, 6H), 0.96 (M, 3H), 1.05 (t, 3H), 1.10-1.45(m, 8H), 1.51 (m, 2H), 1.70-1.85 (m, 5H), 2.10 (m, 1H), 2.20-2.60 (m,4H), 2.70-2.90 (m, 4H), 3.20 (m, 2H), 3.78 (m, 1H).

-   3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 388.3 (M+1)

¹H-NMR (CDCl₃): d 1.02 (m, 3H), 1.20-2.40 (m, 32H), 2.70-3.00 (m, 3H),3.25 (m, 2H), 3.78 (m, 1H).

-   3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2-2H-benzimidazol-2-one

MS: m/z 362.3 (M+1)

¹H-NMR (CDCl₃): d 1.03 (m, 3H), 1.25-1.90 (m, 24H), 2.02 (m, 1H), 2.30(m, 3H), 2.60 (m, 1H), 2.70-2.90 (m, 4H), 3.20 (m, 2H), 3.75 (m, 1H).

-   3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 376.3 (M+1)

¹H-NMR (CDCl₃): d 0.85 (d, 6H), 1.05 (t, 3H), 1.25-1.90 (m, 20H),1.99-2.35 (m, 5H), 2.73 (m, 1H), 2.85 (m, 1H), 3.00 (m, 2H), 3.20 (m,2H), 3.75 (m, 1H).

-   3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

MS: m/z 376.3 (M+1)

¹H-NMR (CDCl₃): d 1.05 (t, 3H), 1.10-2.10 (m, 30H), 2.27 (m, 1H), 2.74(m, 1H), 2.85 (m, 3H), 3.20 (m, 2H), 3.75 (m, 1H).

EXAMPLE 4

Nociceptin affinity at the ORL1 receptor for preferred compounds wasobtained using the following assay:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like receptor (ORL-1) (Receptor Biology) were prepared bylysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/teflon pestle. Membranes were collected by centrifugation at30,000× g for 15 min at 4° C. and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrationswere determined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

Functional SGTPgS binding assays were conducted as follows. ORL-1membrane solution was prepared by sequentially adding finalconcentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin,3 mM GDP and 0.20 nNM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190ml/well) was transferred to 96-shallow well polypropylene platescontaining 10 ml of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at room temperature withshaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 ml ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty ml/wellscintillation cocktail (BetaScint; Wallac) was added and plates werecounted in a Packard Top-Count for 1 min/well.

Data was analyzed using the curve fitting functions in GraphPad PRISMÔ,v. 3.0 and the results are set forth in table 1 below: TABLE 1Nociceptin Affinity calc K_(i) Compound (nM)1-[1-benzyl-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H- 1054benzimidazol-2-one1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 1259octahydro-2H-benzimidazol-2-one1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans- 4371,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 634octahydro-2H-benzimidazol-2-one1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 414octahydro-2H-benzimidazol-2-one1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans- 511,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one1-[1-(cyclooctyl)-4-piperidinyl]-1,3,4,5,6,7,8,9-trans- 125octahydro-2H-benzimidazol-2-one1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-trans- 391,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 16octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(benzyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 692octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans- 8241,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans- 43581,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans- 12391,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans- 4101,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans- 1841,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 111octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans- 891,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans- 111,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one

EXAMPLE 5

Affinity at the μ receptor for compounds was obtained according to thefollowing assay:

Mu opioid receptor membrane solution was prepared by sequentially addingfinal concentrations of 0.075 μg/μl of the desired membrane protein, 10μg/ml saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mMNaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membranesolution (190 μl/well) was transferred to 96-shallow well polypropyleneplates containing 10 μl of 20× concentrated stock solutions of agonistprepared in DMSO. Plates were incubated for 30 min at room temperaturewith shaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 μl ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty μl/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

Data were analyzed using the curve fitting functions in GraphPad PRISM™,v. 3.0 and the results for several compounds are set forth in table 2below: TABLE 2 Mu Receptor Affinity calc K_(i) Compound (nM)1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 1237octahydro-2H-benzimidazol-2-one1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 435octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans- 2791,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9- 909octahydro-2H-benzimidazol-2-one

1. A compound of the formula (I):

wherein A is a saturated or partially saturated ring; R is hydrogen,C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkylC₁₋₄alkyl-, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy-, C₁₋₁₀ alkyl substituted with 1-3 halogen, C₃₋₁₂cycloalkyl substituted with 1-3 halogen, C₃₋₁₂ cycloalkylC₁₋₄alkyl-substituted with 1-3 halogen, C₁₋₁₀ alkoxy substituted with 1-3 halogen,C₃₋₁₂ cycloalkoxy- substituted with 1-3 halogen, —COOV₁, —C₁₋₄COOV₁,—CH₂OH, —SO₂N(V₁)₂, hydroxyC₁₋₁₀alkyl-, hydroxyC₃₋₁₀cycloalkyl-,cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-, —CON(V₁)₂, NH₂SO₂C₁₋₄alkyl-,NH₂SOC₁₋₄alkyl-, sulfonylaminoC₁₋₁₀alkyl-, diaminoalkyl-,-sulfonylC₁₋₄alkyl, a 6-membered heterocyclic ring, a 6-memberedheteroaromatic ring, a 6-membered heterocyclicC₁₋₄alkyl-, a 6-memberedheteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a 6-memberedaromaticC₁₋₄alkyl-, a 5-membered heterocyclic ring optionallysubstituted with an oxo or thio, a 5-membered heteroaromatic ring, a5-membered heterocyclicC₁₋₄alkyl- optionally substituted with an oxo orthio, a 5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₅(═O)W₁, —C₁₋₅(═NH)W₁,—C₁₋₅NHC(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, wherein W₁ is hydrogen,C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH,amino, C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a 5-memberedheteroaromatic ring optionally substituted with 1-3 lower alkyl; whereineach V₁ is independently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,benzyl and phenyl; n is an integer from 0 to 3; M₁, M₂, M₃ and M₄ areeach independently N, NH, CH or CH₂, up to a maximum of 3 N or NH; D, Band C are independently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH, —NHSO₂, hydroxyC₁₋₁₀alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,acylamino-, acylaminoalkyl-, amide, sulfonylaminoC₁₋₁₀alkyl-, or D-B cantogether form a C₂₋₆ bridge, or B-C can together form a C₃₋₇ bridge, orD-C can together form a C₁₋₅ bridge; Z is selected from the groupconsisting of a bond, straight or branched C₁₋₆ alkylene, —NH—, —CH₂O—,—CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, —CH₂CO—, —COCH₂—,—CH₂COCH₂—, —CH(CH₃)—, —CH═, —O— and —HC═CH—, wherein the carbon and/ornitrogen atoms are unsubstituted or substituted with one or more loweralkyl, hydroxy, halo or alkoxy group; R₁ is selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl,amino, C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁,cyano, cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—,NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, aminocarbonyl-,C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-, benzyl, C₃₋₁₂cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroarylring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and aspiro ring system of the formula (II):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; and wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, or benzyl of R₁ is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl-,cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-membered heteroaromaticC₀₋₄alkyl-,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl-, C₁₋₁₀ alkoxy-, and cyano; andwherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, or spiro ring system of the formula (II) isoptionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano; R₂ is selected from the group consistingof hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl- and halogen, said alkyl orcycloalkyl optionally substituted with an oxo, amino, alkylamino ordialkylamino group; or a pharmaceutically acceptable salt thereof orsolvate thereof.
 2. A compound of claim 1, wherein R is —CH₂C═ONH₂,—C(NH)NH₂, pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl,—C(═O)CH₃, —CH₂CH₂NHC(═O)CH₃, —SO₂CH₃, CH₂CH₂NHSO₂CH₃, furanylcarbonyl-,methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-,trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, ordiazolemethyl-.
 3. A compound of claim 1, wherein ZR₁ iscyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-,dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-,thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-,methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-,indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-,hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, oroxocanylpropyl-.
 4. A compound of claim 1, wherein at least one of ZR₁or R is —CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-,NH₂SOmethyl-, aminocarbonylmethyl-, C₁₋₄alkylaminocarbonylmethyl-, ordiC₁₋₄alkylaminocarbonylmethyl-.
 5. A compound of claim 1, wherein ZR₁is 3,3 diphenylpropyl optionally substituted at the 3 carbon of thepropyl with —COOV₁, tetrazolylC₀₋₄alkyl-, cyano-, aminocarbonyl-,C₁₋₄alkylaminocarbonyl-, or diC₁₋₄alkylaminocarbonyl-.
 6. A compound ofthe formula (IA):

wherein A is a saturated or partially saturated ring; n is an integerfrom 0 to 3; Z is selected from the group consisting of a bond, —CH₂—,—NH—, —CH₂O—, —CH₂CH₂—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—,—NHCH₂CO—, —CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, and —HC═CH—,wherein the carbon and/or nitrogen atoms are unsubstituted orsubstituted with a lower alkyl, halogen, hydroxy or alkoxy group; R isselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, and C₃₋₁₂cycloalkyl; R₁ is selected from the group consisting ofhydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino,C₁₋₁₀alkylamino, C₃₋₁₂cycloalkylamino, benzyl, C₃₋₁₂ cycloalkenyl, amonocyclic, bicyclic or tricyclic aryl or heteroaryl ring, aheteromonocyclic ring, a heterobicyclic ring system, and a spiro ringsystem of the formula (II):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino, C₃₋₁₂cycloalkylamino, or benzyl is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl, cyano,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, and cyano; whereinsaid C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclic ortricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclicring system, and spiro ring system of the formula (II) are optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl, phenyl,benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxyand benzyloxy are optionally substituted with 1-3 substituents selectedfrom the group consisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, andcyano; R₂ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl and halogen, said alkyl optionally substitutedwith an oxo group; or a pharmaceutically acceptable salt thereof.
 7. Acompound of claim 6, wherein R₁ is alkyl selected from the groupconsisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.
 8. Acompound of claim 6, wherein R₁ is cycloalkyl selected from the groupconsisting of cyclohexyl, cycloheptyl, cyclodctyl, cyclononyl,cyclodecyl, and norbornyl.
 9. A compound of claim 6, wherein R₁ istetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl.
 10. Acompound of claim 6, wherein R₁ is phenyl or benzyl.
 11. A compound ofclaim 6, wherein R₁ is a bicyclic aromatic ring.
 12. A compound of claim11, wherein R₁ is indenyl, quinoline or naphthyl.
 13. A compound ofclaim 6, wherein Z is a bond, methyl, or ethyl.
 14. A compound of claim6, wherein n is
 0. 15. A compound of claim 6, wherein A is a saturatedring.
 16. A compound of claim 6, wherein X₁ and X₂ are both O.
 17. Acompound selected from the group consisting of:1-[1-benzyl-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(benzyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-trans-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-benzyl-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(4-propylcyclohexyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(5-methylhex-2-yl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(cyclooctyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;1-[1-(cyclooctylmethyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(benzyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;3-ethyl-1-[1-(cyclooctylmethyl)-4-piperidinyl]-cis-1,3,4,5,6,7,8,9-octahydro-2H-benzimidazol-2-one;and pharmaceutically acceptable salts thereof.
 18. A pharmaceuticalcomposition comprising a compound of claim 1 and at least onepharmaceutically acceptable excipient.
 19. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim
 1. 20. A method ofmodulating a pharmacological response from the ORL1 receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 1. 21. A pharmaceutical compositioncomprising a compound of claim 6 and at least one pharmaceuticallyacceptable excipient.
 22. A method of treating pain comprisingadministering to a patient in need thereof, an effective amount of ananalgesic compound according to claim
 6. 23. A method of modulating apharmacological response from the ORL1 receptor comprising administeringto a patient in need thereof, an effective amount of a compoundaccording to claim
 6. 24. A compound of the formula (IA):

wherein R is selected from the group consisting of hydrogen, C₁₋₁₀ alkylC₁₋₁₀ alkoxy, and C₃₋₁₂cycloalkyl; R₂ is selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl and halogen, saidalkyl optionally substituted with an oxo group; A is a saturated orpartially saturated ring; n is an integer from 0 to 3; and ZR₁ is

wherein Y₁ is R₃—(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl,R₆—(C₃-C₁₂)cyclo-alkyl, R₇—(C₃-C₇)heterocycloalkyl, —CO₂(C₁-C₆)alkyl, CNor —C(O)NR₈R₉; Y₂ is hydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; orY₁, Y₂ and Y₃, together with the carbon to which they are attached, formone of the following structures:

wherein r is 0 to 3; w and u are each 0-3, provided that the sum of wand u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring Eis a fused R₄-phenyl or R₅-heteroaryl ring; R₁₀ is 1 to 3 substituentsindependently selected from the group consisting of H, (C₁-C₆)alkyl,—OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ and —(C₁-C₆)alkyl-NR₈R₉; R₁₁ is 1 to 3substituents independently selected from the group consisting of R₁₀,—CF₃, —OCF₃, NO₂ and halo, or R₁₁ substituents on adjacent ring carbonatoms may together form a methylenedioxy or ethylenedioxy ring; R₈ andR₉ are independently selected from the group consisting of hydrogen,(C₁-C₆) alkyl, (C₃-C₁₋₂)cycloalkyl, aryl and aryl(C₁-C₆)alkyl; R₃ is 1to 3 substituents independently selected from the group consisting of H,R₄-aryl, R₆—(C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈R₉, —OR₁₂ and —S(O)₀₋₂R₁₂; R₆ is 1 to 3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, R₄-aryl, —NR₈R₉, —OR₁₂ and —SR₁₂; R₄ is 1 to 3substituents independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, —CN, —CF₃,—OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉, —(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈,—SO₂N(R₁₄)₂, —SO₂R₈, —SOR₈, —NO₂, —CONR₈R₉, —NR₉COR₈, —COR₈, —COCF₃,—OCOR₈, —OCO₂R₈, —COOR₈, —(C₁-C₆)alkyl-NHCOOC(CH₃)₃,—(C₁-C₆)alkyl-NHCOCF₃, —(C₁-C₆)atkyl-NHSO₂—(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NHCONH-(C₁-C₆)-alkyl and

wherein f is 0 to 6; or R₄ substituents on adjacent ring carbon atomsmay together form a methylenedioxy or ethylenedioxy ring; R₅ is 1 to 3substituents independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, —CN, —CF₃,—OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉, —(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈,—SO₂N(R₁₄)₂, —NO₂, —CONR₈R₉, —NR₉COR₈, —COR₈, —OCOR₈, —OCO₂R₈ and—COOR₈; R₇ is H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ or—(C₁-C₆)alkyl-NR₈R₉; R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, —(C₁-C₆)alkyl-OR₈,—(C₁-C₆)alkyl-NR₈R₉, —(C₁-C₆)alkyl-SR₈, or aryl (C₁-C₆)alkyl; R₁₃ is 1-3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo; R₁₄ is independently selected fromthe group consisting of H, (C₁-C₆)alkyl and R₁₃—C₆H₄—CH₂—; or apharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising a compound of claim 24 and at least onepharmaceutically acceptable excipient.
 26. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim
 24. 27. A method ofmodulating a pharmacological response from the ORL1 receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 24. 28. A method of modulating apharmacological response from an opioid receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 1. 29. A method of modulating apharmacological response from an opioid receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 6. 30. A method of modulating apharmacological response from an opioid receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim 24.